Pigment epithelium‐derived factor (PEDF) protects neurons from oxidant injury by activation of extracellular signal‐regulated kinase (ERK) 1/2 and induction of Bcl‐2

Abstract

Oxidative stress is an important trigger in the chain of events leading to neuronal death. Mitigating oxidative‐induced damage is critical to preserving neuronal function in injury and disease. Studies show that PEDF imparts protection for retinal neurons and recently also for cerebral cortical cultures. The mechanisms underlying its protective effects have not been elucidated. The current study aims to determine the mechanisms contributing to the neuroprotective effect of PEDF in cortical neurons. Cultured primary neurons are exposed to increasing doses of H2O2 and PEDF with or without an ERK 1/2 inhibitor (U0126) or PI‐3K/Akt inhibitor (LY294002). Levels of the anti‐apoptotic protein Bcl‐2 and phosphorylated ERK1/2, as well as cell survival are determined. H2O2 treatment decreases neuron survival and release of PEDF. Exogenous PEDF induces a dose‐dependent increase in Bcl‐2 and neuronal survival. PEDF pre‐treatment prevents the H2O2‐mediated decrease in cell survival and this effect is blocked by both U0126 and LY294002. PEDF pre‐treatment also prevents the H2O2‐induced decrease in Bcl‐2 which is blocked by U0126 but not by LY294002. These results demonstrate that PEDF protection against H2O2 ‐induced injury is mediated by ERK1/2 induction of Bcl‐2 and suggest that PEDF can protect neurons from oxidative stress. This work was supported, in part, by grants from the NIH (AG15964, AG020569 and AG028367).